Sunday, March 4, 2007 - 12:00 AM
Will FDA put humans at risk with cow drug?
By Rick Weiss
The Washington Post
The government is on track to approve a new antibiotic to treat a pneumonialike disease in cattle, despite warnings from health groups and a majority of the agency's own expert advisers that the decision will be dangerous for people.
The drug, cefquinome, belongs to a class of potent antibiotics that are among medicine's last defense against several serious human infections. No drug from that class has been approved in the United States for use in animals.
The American Medical Association and about 12 other health groups warned the Food and Drug Administration that giving cefquinome to animals probably would speed the emergence of microbes resistant to that important class of antibiotic, as has happened with other drugs. Those supermicrobes could then spread to people.
Echoing those concerns, the FDA's advisory board last fall voted to reject the request by Intervet of Millsboro, Del., to market the drug for cattle.
Yet by all indications, the FDA will approve cefquinome this spring. That outcome is all but required, officials said, by a recently implemented "guidance document" that codifies how to weigh threats to human health posed by proposed new animal drugs.
The wording of "Guidance for Industry 152" was crafted within the FDA after a long struggle. In the end, the agency adopted language that, for drugs such as cefquinome, is more deferential to pharmaceutical companies than is recommended by the World Health Organization.
Industry representatives said they trust Guidance 152's calculation that cefquinome should be approved. "There is reasonable certainty of no harm to public health," Carl Johnson, Intervet's director of product development, told the FDA last fall.
But others said Guidance 152 makes it too difficult for the FDA to say "no" to some drugs.
"The industry says that 'Until you show us a direct link to human mortality from the use of these drugs in animals, we don't think you should preclude their use,' " said Edward Belongia, an epidemiologist at the Marshfield Clinic Research Foundation in Wisconsin. "But do we really want to drive more resistance genes into the human population? It's easy to open the barn door, but it's hard to close the door once it's open."
Previous problems
The FDA knows how hard it can be to close that door. In the mid-1990s, overriding the objections of public-health experts from the Centers for Disease Control and Prevention (CDC), the drug agency approved the marketing of two drugs, Baytril and Saraflox, for use in poultry.
Both are fluoroquinolones, a class of drugs important for their ability to fight the bacterium that causes anthrax and a food-borne bacterium called campylobacter, which causes a serious diarrheal disease in people.
Before long, doctors began finding fluoroquinolone-resistant strains of campylobacter in patients hospitalized with severe diarrhea. When studies showed a link to poultry, the FDA sought a ban. But while Abbott Laboratories, which made Saraflox, pulled its product, Baytril's manufacturer, Bayer, pushed back.
"They fought this tooth and nail. It took years," said Kirk Smith, an epidemiologist at the Minnesota Department of Health.
Finally, late in 2005, Bayer gave up, but not before fluoroquinolone resistance had spread further.
Bugs evolve constantly
Microbes are constantly mutating, and some of those mutations happen to confer immunity to one drug or another. Exacerbating the problem, bacteria constantly exchange bits of DNA with one another, spreading that resistance.
Given those realities, experts agree that all antibiotics should be used judiciously.
"If a drug is used less, then less resistance emerges," said Patricia Griffin, chief of the CDC's enteric-disease epidemiology branch.
Prudence is especially important for medicines of last resort, which is why the cefquinome application stirred such a storm.
Cefquinome is a fourth-generation cephalosporin, the most recent of several steadily improving versions of that family of antibiotics. Only one medicine from that family has been approved in the United States, a powerful drug for humans, cefepime (brand name Maxipime), which is the only effective treatment for serious infections in cancer patients and a reliable lifesaver against several other nearly invincible infections.
Intervet invented cefquinome to treat bovine respiratory disease, the most common disease in cattle. Recognizing the potential public-health implications of using a close cousin of cefepime in animals, the FDA's Center for Veterinary Medicine, which oversees animal-drug approvals, convened its expert advisers in September.
One of the first things the group learned was that more than 12 medicines are on the market for the respiratory syndrome, and all are effective.
"If we have no susceptibility problem, why do we need one more new drug?" asked James Leggett, a professor of medicine at Oregon Health & Science University the FDA brought in as a consultant on the cefquinome question.
The panel also learned the disease would be a relatively minor issue but for the conditions under which U.S. cattle are raised, including high-density living and routine shipment on crowded trains for hundreds or thousands of miles, both of which suppress the animals' immune systems.
Yet Stephen Sundlof, head of the FDA's Veterinary Medicine Center, told the panel that under FDA rules, members should ignore those issues and consider only the language in Guidance 152.
Risk criteria argued
After the Baytril debacle, the public-health community embraced the idea of a guidance document. A formalized risk-assessment process promised to minimize the chances of making a bad regulatory call.
But a struggle ensued over the criteria to be used for measuring risk, with veterinarians and veterinary-drug companies often on one side and doctors and public-health experts on the other.
When differences could not be resolved, the FDA sidestepped some tough issues and adopted language both sides agree can block approval of the most worrisome drugs, those such as Baytril that are put in animal feed or water, and so are easily overused. But public-health experts said the wording favors industry for other kinds of drugs and want it revised.
They noted the guidance makes it almost impossible to say no to a new animal drug unless it is likely to threaten the effectiveness of an antibiotic that is a critical player against food-borne illnesses.
The World Health Organization recommends saying no if approval would spur resistance to any antibiotic that is important for fighting "serious human disease," not just food-borne illnesses.
Cefquinome's primary threat is that it may undermine the usefulness of the closely related human drug, cefepime. But the FDA does not consider cefepime a front-line drug against food-borne infections.
So although it is a highly important drug in human medicine — and although the Infectious Diseases Society of America recommends it against some food-borne bacteria — that risk does not count under the terms of Guidance 152.
Moreover, 152 does not take into account that when microbes become resistant to fourth-generation cephalosporins, they often gain resistance to third-generation versions.
Third-generation cephalosporins are among the only effective therapies for serious gastrointestinal diseases in children and are the sole therapies for many cases of meningitis.
That means the emergence of resistance to fourth-generation cephalosporins "could have a much more far-reaching effect" than is considered under the terms of Guidance 152, John Powers, a medical officer at the FDA's Center for Drug Evaluation and Research, told the agency's expert panel.
The Animal Health Institute, which represents veterinary drugmakers, argues that the risk to human health posed by animal antibiotics has been overblown.
Officials at Intervet declined several requests to be interviewed. In a statement, the company said it "fully supports the prudent use of antibiotics in animals."
The statement also says that in Europe, fourth-generation cephalosporins similar to cefquinome have been used in animals for the past decade "without compromising the interests of public health."
Yet recent European data indicate resistance against this class of antibiotics is on the rise.
An analysis of E. coli bacteria in pigs and other animals in Spain, published in December, found high levels of the resistance that renders fourth-generation cephalosporins useless. And a January report from Great Britain documented similar resistance patterns emerging at 10 farms.
At the FDA advisory meeting in September, the agency's experts defied Guidance 152 and voted six to four against approval of cefquinome. But that day, and in follow-up interviews, Sundlof, the agency's veterinary chief, made it plain the vote was "not binding."
Copyright © 2007 The Seattle Times Company
Will FDA put humans at risk with cow drug?
By Rick Weiss
The Washington Post
The government is on track to approve a new antibiotic to treat a pneumonialike disease in cattle, despite warnings from health groups and a majority of the agency's own expert advisers that the decision will be dangerous for people.
The drug, cefquinome, belongs to a class of potent antibiotics that are among medicine's last defense against several serious human infections. No drug from that class has been approved in the United States for use in animals.
The American Medical Association and about 12 other health groups warned the Food and Drug Administration that giving cefquinome to animals probably would speed the emergence of microbes resistant to that important class of antibiotic, as has happened with other drugs. Those supermicrobes could then spread to people.
Echoing those concerns, the FDA's advisory board last fall voted to reject the request by Intervet of Millsboro, Del., to market the drug for cattle.
Yet by all indications, the FDA will approve cefquinome this spring. That outcome is all but required, officials said, by a recently implemented "guidance document" that codifies how to weigh threats to human health posed by proposed new animal drugs.
The wording of "Guidance for Industry 152" was crafted within the FDA after a long struggle. In the end, the agency adopted language that, for drugs such as cefquinome, is more deferential to pharmaceutical companies than is recommended by the World Health Organization.
Industry representatives said they trust Guidance 152's calculation that cefquinome should be approved. "There is reasonable certainty of no harm to public health," Carl Johnson, Intervet's director of product development, told the FDA last fall.
But others said Guidance 152 makes it too difficult for the FDA to say "no" to some drugs.
"The industry says that 'Until you show us a direct link to human mortality from the use of these drugs in animals, we don't think you should preclude their use,' " said Edward Belongia, an epidemiologist at the Marshfield Clinic Research Foundation in Wisconsin. "But do we really want to drive more resistance genes into the human population? It's easy to open the barn door, but it's hard to close the door once it's open."
Previous problems
The FDA knows how hard it can be to close that door. In the mid-1990s, overriding the objections of public-health experts from the Centers for Disease Control and Prevention (CDC), the drug agency approved the marketing of two drugs, Baytril and Saraflox, for use in poultry.
Both are fluoroquinolones, a class of drugs important for their ability to fight the bacterium that causes anthrax and a food-borne bacterium called campylobacter, which causes a serious diarrheal disease in people.
Before long, doctors began finding fluoroquinolone-resistant strains of campylobacter in patients hospitalized with severe diarrhea. When studies showed a link to poultry, the FDA sought a ban. But while Abbott Laboratories, which made Saraflox, pulled its product, Baytril's manufacturer, Bayer, pushed back.
"They fought this tooth and nail. It took years," said Kirk Smith, an epidemiologist at the Minnesota Department of Health.
Finally, late in 2005, Bayer gave up, but not before fluoroquinolone resistance had spread further.
Bugs evolve constantly
Microbes are constantly mutating, and some of those mutations happen to confer immunity to one drug or another. Exacerbating the problem, bacteria constantly exchange bits of DNA with one another, spreading that resistance.
Given those realities, experts agree that all antibiotics should be used judiciously.
"If a drug is used less, then less resistance emerges," said Patricia Griffin, chief of the CDC's enteric-disease epidemiology branch.
Prudence is especially important for medicines of last resort, which is why the cefquinome application stirred such a storm.
Cefquinome is a fourth-generation cephalosporin, the most recent of several steadily improving versions of that family of antibiotics. Only one medicine from that family has been approved in the United States, a powerful drug for humans, cefepime (brand name Maxipime), which is the only effective treatment for serious infections in cancer patients and a reliable lifesaver against several other nearly invincible infections.
Intervet invented cefquinome to treat bovine respiratory disease, the most common disease in cattle. Recognizing the potential public-health implications of using a close cousin of cefepime in animals, the FDA's Center for Veterinary Medicine, which oversees animal-drug approvals, convened its expert advisers in September.
One of the first things the group learned was that more than 12 medicines are on the market for the respiratory syndrome, and all are effective.
"If we have no susceptibility problem, why do we need one more new drug?" asked James Leggett, a professor of medicine at Oregon Health & Science University the FDA brought in as a consultant on the cefquinome question.
The panel also learned the disease would be a relatively minor issue but for the conditions under which U.S. cattle are raised, including high-density living and routine shipment on crowded trains for hundreds or thousands of miles, both of which suppress the animals' immune systems.
Yet Stephen Sundlof, head of the FDA's Veterinary Medicine Center, told the panel that under FDA rules, members should ignore those issues and consider only the language in Guidance 152.
Risk criteria argued
After the Baytril debacle, the public-health community embraced the idea of a guidance document. A formalized risk-assessment process promised to minimize the chances of making a bad regulatory call.
But a struggle ensued over the criteria to be used for measuring risk, with veterinarians and veterinary-drug companies often on one side and doctors and public-health experts on the other.
When differences could not be resolved, the FDA sidestepped some tough issues and adopted language both sides agree can block approval of the most worrisome drugs, those such as Baytril that are put in animal feed or water, and so are easily overused. But public-health experts said the wording favors industry for other kinds of drugs and want it revised.
They noted the guidance makes it almost impossible to say no to a new animal drug unless it is likely to threaten the effectiveness of an antibiotic that is a critical player against food-borne illnesses.
The World Health Organization recommends saying no if approval would spur resistance to any antibiotic that is important for fighting "serious human disease," not just food-borne illnesses.
Cefquinome's primary threat is that it may undermine the usefulness of the closely related human drug, cefepime. But the FDA does not consider cefepime a front-line drug against food-borne infections.
So although it is a highly important drug in human medicine — and although the Infectious Diseases Society of America recommends it against some food-borne bacteria — that risk does not count under the terms of Guidance 152.
Moreover, 152 does not take into account that when microbes become resistant to fourth-generation cephalosporins, they often gain resistance to third-generation versions.
Third-generation cephalosporins are among the only effective therapies for serious gastrointestinal diseases in children and are the sole therapies for many cases of meningitis.
That means the emergence of resistance to fourth-generation cephalosporins "could have a much more far-reaching effect" than is considered under the terms of Guidance 152, John Powers, a medical officer at the FDA's Center for Drug Evaluation and Research, told the agency's expert panel.
The Animal Health Institute, which represents veterinary drugmakers, argues that the risk to human health posed by animal antibiotics has been overblown.
Officials at Intervet declined several requests to be interviewed. In a statement, the company said it "fully supports the prudent use of antibiotics in animals."
The statement also says that in Europe, fourth-generation cephalosporins similar to cefquinome have been used in animals for the past decade "without compromising the interests of public health."
Yet recent European data indicate resistance against this class of antibiotics is on the rise.
An analysis of E. coli bacteria in pigs and other animals in Spain, published in December, found high levels of the resistance that renders fourth-generation cephalosporins useless. And a January report from Great Britain documented similar resistance patterns emerging at 10 farms.
At the FDA advisory meeting in September, the agency's experts defied Guidance 152 and voted six to four against approval of cefquinome. But that day, and in follow-up interviews, Sundlof, the agency's veterinary chief, made it plain the vote was "not binding."
Copyright © 2007 The Seattle Times Company
